ALZHEIMER’S UPDATE:
hopefully exciting news is on the way

The three huge diseases affecting us are:

1. Cardiovascular disease

2. Cancer

3. Dementia (85% is due to Alzheimer’s.) One million people in the UK currently have Alzheimer’s, expected to rise to 1.4 million by 2040

For Alzheimer’s, seeing a doctor as early as possible when you have what is called mild cognitive impairment is essential, as that is when the treatments will make much the largest difference. We are very limited once the more severe spectrum of the disease is reached.  

In July 2024 I sent out a bulletin on Alzheimer’s which you can see on our website 90sloanestreet.com On the Tabs clinical news, dropdown - Alzheimer’s (at the bottom of the list.) Read article           

You may wish to read this article to give you the full context. 

The key aspects of the bulletin were:

1.  We now have tests that can predict future Alzheimer’s risk -10 years maybe 15-20 years ahead of its development. This is an extraordinary benefit giving the opportunity to start treatments at an early stage when they will likely make the largest difference.

2.  Two new anti-amyloid removers approved for use: donanemab and lecanemab

3.  An anti-tau drug “hopeful” HMTM - not yet licensed.

The Pathology

In the presence of amyloid, tau protein starts to spread logout the brain and the tau explosion kills your brain cells. Amyloid can be present for a decade before the spread of tau. Early detection of the amyloid load is what we are looking for. In summary, the pathology includes extracellular amyloid plaques and intra neuronal neurofibrillary tangles and loss of neurons and synapses. Misfolding and aggregation of tau proteins and the subsequent formation of tau tangles disrupt neuronal function.

reproduced from  Neurology 2013; 80(19): 1778-83.

pTau 217 blood biomarker for Alzheimer’s

Recently I did some work with the BBC about a blood test pTau 217 - a marker of amyloid brain load. I was involved in a trial -BioHermes - with a special friend Dr Emer MacSweeney, who is the remarkable founder of Re:cognition Health specialising in Dementia.  In an ITN news interview two weeks ago I shared that I would not advise symptom free people to take the test as yet, stating that we need greater proof that we have effective treatments that are cost viable. Currently, treatment with the amyloid strippers is for about 18 months, so as to completely clear the brain. The cost of the medicines, infusions and MRI scans is a considerable £65-70,000 per year.  

My bulletin went on to describe that currently the most frequently used treatments prescribable in the NHS are aricept or donepezil, memantine and galantamine. All of these improve connectivity between brain cells – neurons - by raising the level of the transmitter acetyl choline. However, this type of medicine does not stop brain cell death – so sadly they do not affect the disease process – they are acting as metaphorical sticking plasters.

The real goal is to stop brain cells from dying. There are two main proteins involved in the death of brain cells: amyloid and tau.

The anti-amyloid drugs lecanemab and donanemab were both licensed in 2024 and can now be prescribed privately, whilst simultaneously the government advised they were too expensive for the NHS to prescribe.

Progress over the last two years

Amyloid removal medicines

There has been a shift at Re:cognition Health to using donanemab 4 weekly rather than lecanemab which is given as an infusion two -weekly. Earlier trials suggested donanemab was the most effective, but it had more associated brain bleeds – ARIA H (amyloid-related imaging abnormality-haemorrhage.) This is the main risk of the amyloid strippers and why MRI scans are done between infusions, to check if the treatment should be reduced or delayed. There is an art to this, and we feel Re:cognition health, with Emer MacSweeney leading her remarkable organisation is best placed, and has the largest amount of experience. Emer is now able to give donanemab to patients who were previously contraindicated. Those so-called APOE4 homozygous - the term meaning both pairs of the gene - have the change, giving a much higher risk of brain bleeds.  

Amyloid removers cannot  be given to patients on anticoagulants such as apixaban, for atrial  fibrillation, as the risk of bleeding is too high. (In another space, I can  give you some encouragement from the Ocean Study in atrial fibrillation.)

The vitally needed second medicine type is anti-tau

In 2024 I was enthusiastic that HMTM - an anti-tau drug - given orally with no risk of bleeds and almost nothing in the way of side effects other than colouring your pee blue – would hopefully be licensed. However, it has been coming up for 20 months waiting for the MHRA to make their decision to license it or not. There would be two main criteria: is it safe and is there clear statistical evidence it works? Lastly in terms of the NHS, is it cost effective?

In this wilderness I have felt a little worried about whether my enthusiasm for HMTM has been too much. But suddenly to my surprise at midnight two weekends ago, I came across a new paper publication on it.

The problem HMTM has had is that as it makes your urine blue so the company decided the only way of not revealing who was on the active drug was to use a small dose as placebo. The serious problem has been that it seems that the small dose worked, so making it difficult to achieve proof of efficacy.

HMTM is produced by a company called Taurx. Interestingly their website seems to have tripled in size in the last few weeks, which is surely an encouraging sign. 

I do hope this paper will carry it across the line for being licensed as there are certainly no safety concerns that I can see. While i am not suggesting it is as substantial as penicillin’s discovery, it is really major and exciting for the future that we may be at a point of changing this really horrendous disease.

Summarised below are Taurx’s comments on their latest paper taken from their website.

A phase 3 trial called - Lucidity - evaluating the efficacy and safety of HMTM in the treatment of mild cognitive impairment due to Alzheimer’s disease has been published.

The trial reports that participants with mild cognitive impairment (MCI) who received HMTM 16 mg/day experienced statistically significant cognitive improvement over 18 months, with no significant cognitive or functional decline observed over a period of 2 years.  

The study also found starting HMTM treatment early in the disease process is important for the preservation of cognitive function and that it impacts the underlying disease process in AD.

This study confirms results from earlier trials showing that HMTM has a benign safety profile, with headache (1.5%) and diarrhoea (1.2%) reported as the most frequent adverse effects. 

The trial evaluated the safety and efficacy of HMTM in 598 participants with MCI and mild to moderate dementia due to Alzheimer’s disease (AD). All participants were amyloid β-PET positive, with 44% (263) meeting the clinical criteria for MCI due to Alzheimer’s disease, and 56% (335) diagnosed with mild to moderate dementia due to AD. 

The paper, entitled Clinical, imaging and blood biomarker outcomes in a Phase 3 clinical trial of tau aggregation inhibitor hydromethylthionine mesylate in mild cognitive impairment and mild to moderate dementia due to Alzheimer’s disease, reports on the trial which was conducted at 82 sites across Canada, the European Union, United Kingdom, and United States.

It compared 16 mg/day and 8 mg/day doses of HMTM with 4 mg twice weekly doses of methylthioninium chloride (MTC). MTC was required as a urinary colourant to preserve blinding due to possible urinary discolouration caused by HMTM. 

In the trial, HMTM and MTC were compared on cognitive and functional endpoints for the first 52 weeks followed by all patients receiving HMTM 16 mg/day to 104 weeks in a modified delayed-start trial design. Unexpected initial symptomatic activity in the MTC arm interfered with the intended primary outcome analyses at 52 weeks, but not with longer-term outcomes in participants with MCI. 

MCI participants receiving HMTM 16 mg/day showed statistically significant differences in cognitive decline (ADAS-cog13) at 78 weeks and 104 weeks in analyses specified prior to the 104-week database lock. Those starting HMTM 16 mg/day after a 52-week delay could not catch up with those starting earlier due to ongoing neurodegeneration during the first 52 weeks in those receiving MTC. 

The benefit of HMTM 16 mg/day has been confirmed in a further study utilising closely matched external placebo arm cases from a well-documented trial database to provide true placebo controls not confounded by the blinding problem.

The study confirms the results from earlier trials showing that HMTM has a benign safety profile, with headache (1.5%) and diarrhoea (1.2%) reported as the most frequent adverse effects on the 16 mg/day dose.

HMTM is an investigational drug and a Marketing Authorisation Application from TauRx Therapeutics Management Ltd is currently being evaluated by the UK’s Medicines and Healthcare products Regulatory Agency (MHRA).

(n is the number of people on treatment)

ADAS -cog

This is a well known scoring system for assessing level of functionality in Alzheimer's

My Comments:

On this chart from their paper, you can see that the black filled-in square box has changed little over the 2 years in terms of cognitive function whereas on the smaller dose of 8mg HMTM the result is a little less good and with the Octagon MTC the placebo there is the expected deterioration.

We see an initial improvement in both the placebo and treatment population which only persists in the 16mg per day treatment group at 2 years, while going down close to baseline at the end.

A fair criticism is that the number of patients is maybe a little small.

But there is such a desperate need and the medicine is so simple just swallowing a tablet - not any infusions and no serial MRI brain scans needed - as it does not cause bleeds.

I do hope they will license it, albeit setting up a larger-scale NHS Trial. Every day more people are starting to develop symptoms – the evidence may not be perfect but to a drowning man you will try anything even a branch and HMTM seems better than that to me.

There are to my knowledge no other anti-tau medicines in trial at present which have any possibility of being on the shelves in the next 3 years.  However, there are at least 28 medicines in pipeline trials at present. The future is bright.

NB this trial is on HMTM alone, not on an anti-amyloid stripper as well. The golden hope and used early, will be the combination of an anti-amyloid and anti-tau drug with the aim of having the most successful and long-lasting effect.  

Those at risk in the future being identified by the pTau 217 testing.  

A really dramatic moment will come this summer when Trailblazer 3 is published:  a trial of the anti-amyloid stripper donanemab in people who have no symptoms at all, but who on testing, have a positive pTau 217 value, showing they are on the way to developing Alzheimer’s in the future.

The other exciting innovation is a new drug called trontinemab, another anti-amyloid removing drug but with a special new mechanism for crossing the blood brain barrier called “brain shuttle.”Will it be more effective than donanemab and what will the number of bleeds be?  TRONTIER 1 and 2 trials of this drug began in late 2025 aiming to enrol 1,600 patients with early symptomatic disease across 18 countries.

A remarkable new treatment recently started at Re:cognition health: Apheresis in Alzheimer's

Apheresis, is emerging as a potential treatment approach for Alzheimer's disease.

It involves removing a patient’s blood plasma and replacing it with donated plasma or albumin, aiming to eliminate harmful substances that may contribute to the progression of AD

Recent studies, including the AMBAR trial (Alzheimer Management by Albumin Replacement), have shown promising preliminary results suggesting that plasma exchange with albumin replacement could slow cognitive and functional decline in Alzheimer's patients. The technique reduces the neurotoxic substances and pathological proteins in the blood that may affect the brain.

Apheresis, is a hopeful and innovative strategy under investigation for Alzheimer's disease, with early evidence supporting its potential to slow disease progression by cleansing harmful blood components.

Early investigations and treatment are crucial. Treatments are likely to be relatively ineffective in late disease due to loss of brain cells.

With grateful thanks to Emer for our many conversations at 7.45 a.m. helping our patients.

In Staying Alive 3 we will look at Hypertension